NO170485B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-ALKYL-SUBSTITUTED BENZIMIDAZOLE DERIVATIVES - Google Patents

Abstract

Novel 1-alkyl substituted benzimidazole derivatives of formula <CHEM> wherein -A<1>=A<2>-A<3>=A<4>- is a bivalent radical having the formula -CH=CH-CH=CH- (a-1), -N=CH-CH=CH- (a-2), -CH=N-CH=CH- (a-3), -CH=CH-N=CH- (a-4), -CH=CH-CH=N- (a-5), -N=CH-N=CH- (a-6), or -CH=N-CH=N- (a-7); B is NR<3>, CH2, O, S, SO or SO2; L is hydrogen, C1-6alkylcarbonyl, C1-6alkylsulfonyl, C1-6alkyloxycarbonyl, Ar<2>-C1-6alkyloxycarbonyl, Ar<2>-carbonyl, Ar<2>-sulfonyl, C3-6cycloalkyl, C2-6alkenyl optionally substituted with Ar<2>, C1-12alkyl, a radical of formula -Alk-R<4> (b-1), -Alk-Y-R<5> (b-2), -Alk-Z<1>-C(X)-Z<2>-R<6> (b-3), or -CH2-CHOH-CH2-O-R<7> (b-4); the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, which compounds are anti-allergic agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.

Description

The present invention relates to an analogue method for the production of therapeutically active 1-alkyl-substituted benzimidazole derivatives.

US-PS 4,219,559 discloses a number of 1-substituted N-heterocyclyl-4-piperidinamines as compounds with useful antihistamine properties.

In US-PS 4,556,660, 4,634,704, 4,695,569 and 4,588,722 further series of N-heterocyclyl-4-piperidinamines are described as compounds with useful antihistamine and serotonin antagonist properties.

Furthermore, it is described in EP publ. 151,826, a number of 4-(bicyclic heterocyclyl)methyl and -heteropiperidines with useful antihistamine and serotonin antagonist properties. In addition, some antihistamines (4-piperidinylmethyl- and

—hetero)purines described in EP publ. 206,415.

Finally, some antihistamine N-1H-benzimidazole-4-piperidinamines are described in "J. Eeterocyclic Chem.", 24. 31 (1987).

The compounds according to the present invention differ from these by the fact that the benzimidazole derivative is always substituted in the 1-position with a hydroxy-, mercapto- or amino-C 1-4 alkyl group which is optionally O-, S- or N-alkylated, and by its favorable pharmacological properties.

The present invention thus relates, as mentioned above, to the production of new 1-alkyl-substituted benzimidazole derivatives with the general formula:

a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein

-A<1>=A^-A^=A^- is a two-valued remainder with the formula

where one or two hydrogen atoms in the residues (a-1) to (a-7) can be independently replaced by halogen, C1-6 alkyl, C1-6 alkyloxy;

R<*> is hydrogen; C 6-6 alkenyl which is optionally substituted with phenyl; C 6 -6 alkynyl; phenyl; substituted phenyl; pyrimidinyl; or C^_^alkyl which is optionally substituted with phenyl, substituted phenyl, thienyl, furanyl, C 1-6 , alkyl substituted furanyl, pyridinyl, pyrimidinyl, hydroxy, C 1-4 alkoxy, carboxyl, C 1-4 alkyloxy carbonyl, phenoxy carbonyl or benzyloxy carbonyl;

G is 0, S or NR<2>;

where R<2> is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl or benzyl;

B is NR<3>, CH2 or 0;

wherein R<3> is hydrogen, C1-6 alkyl or benzyl;

R is hydrogen or C^_^alkyl;

n is 0, 1 or 2;

L is hydrogen, C₁₋alkyloxycarbonyl, C₃₋₋cycloalkyl, C₂₋₋alkenyl which is optionally substituted with phenyl, C₋₋₋alkyl or a residue of the formula

there

R<4> is phenyl, substituted phenyl, Het or cyano;

R<5> is hydrogen, phenyl, substituted phenyl, Het or C1-6 alkyl;

R<6> is hydrogen, phenyl, substituted phenyl, Het or C1-6 alkyl;

R<7> is phenyl, substituted phenyl or naphthalenyl;

Y is 0, S or NH;

Z<1> and Z<2> are each independently 0, S, NH or a direct bond;

X is 0 or S;

each Alk independently is C 1 -3 alkanediyl;

substituted phenyl is phenyl substituted with halogen, hydroxy, amino, C 1-4 alkyloxy or C 1-4 alkyl;

Het is pyridinyl optionally substituted with halogen, amino, C 1-6 alkyl or hydroxy; pyrimidinyl which is optionally substituted with halogen, amino, hydroxy or C 1-6 alkyl; thienyl; furanyl; pyrrolyl optionally substituted with C 1-6 alkyl; thiazolyl optionally substituted with C 1-6 alkyl; imidazolyl which is optionally substituted with C 1-6 alkyl; tetrazolyl which is optionally substituted with C 1-6 alkyl; 1,3,4-thiadiazolyl which is optionally substituted with C 1-6 alkyl; 4,5-dihydro-5-oxo-1H-tetrazolyl which is optionally substituted with C 1-6 alkyl; 2,3-dihydro-1,4-benzodioxynyl; 2-oxo-2E-1-benzopyranyl or a bicyclic residue of the formula

aer

G<2> is -CH=CH-CE=CH-, -S-(CE2)2-, -S-(CH2)3-, -(CE2)4-,

-S-CE=CH- or -S-CE=C(CE3)-; and

R 17 is C 1-6 alkyl;

provided that when L is hydrogen, C 1-4 alkyl or benzyl and R 1 -G-Alk is <C>1-4-alkyloxyethyl, <C>3-4alkenyloxyethyl or phenoxyethyl, then -A^=A<2->A3=A4 - different from a bivalent residue of the formula -CE=CE-CE=CE-.

As used in the preceding definitions, the term halogen is generic for fluorine, chlorine, bromine and iodine; the term "C^_^alkyl" includes straight and branched saturated hydrocarbon residues having from 1 to 6 carbon atoms such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and the like ; the term "C 6 -cycloalkyl" is generic for cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "C 6 -alkenyl" defines straight and branched hydrocarbon residues containing a double bond and with from 2 to 6 carbon atoms such as ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2 -butenyl and the like; "C 8 -6 alkynyl" defines straight and branched hydrocarbon residues containing a triple bond and having from 3 to 6 carbon atoms such as, for example, 2-propyl,

2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl and the like; and when a C 8 -6 alkenyl or a C 3 -6 alkynyl is substituted with a heteroatom, the carbon atom in this C 8 -6 alkenyl or C 8 -6 alkynyl which is connected to the hetero atom is preferably saturated.

It should be clear that the compounds of formula (I) can exist in hydrated or solution addition forms and that the invention is also considered to encompass all such forms.

A special group among the compounds of formula (I) are the compounds of formula (I) provided that when (i) L is hydrogen, C 2-6 alkyl or benzyl and (ii) R<1->G-Alk is C 1-6 alkyloxyethyl, C 2-6 alkenyloxyethyl, Cg_6alkynyloxyethyl or phenoxyethyl, is -A<l>=A<2->A<3=>A<4-> is different from a divalent residue of formula (a-1).

An interesting subgroup among the compounds of formula (I) are those compounds of formula (I) where -A<1>=A<2->A<3=>A4-is a divalent residue of formula (a-1).

Another interesting subgroup among the compounds of formula (I) are those compounds of formula (I) where —A<1>=A<2->A<3>=A<4-> is a divalent residue of the formula (a- 2) to (a-7) while (a-2) is the most interesting subgroup.

Particularly preferred compounds are the preferred compounds where R<1> is hydrogen, C8_^alkenyl, C8_^alkynyl, Ar<*> or C1_^alkyl optionally substituted with carboxyl, G is 0, L is hydrogen, C1_^alkyl or a residue with the formula (b-1), (b-2) or (b-3) and B is NH or CH2.

More particularly preferred compounds are 3-(2-ethoxyethyl)-N-(1-methyl-4-piperidinyl)-3E-imidazo[4,5-b]pyridin-2-amine and 3-(2-ethoxyethyl)-N -[l-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-3H-imidazo-[4,5-b]pyridin-2-amine, pharmaceutically acceptable acid addition salts and the possible stereochemically isomeric forms thereof.

According to the invention, the compounds of formula (I) can be prepared by:

IN.

reaction of a piperidine, pyrrolidine or hexahydro-1H-azepine with the formula

where X<3> is 0, S or NE and W is a reactive cleavable group, with an aromatic diamine with the formula in a reaction-inert medium, the reaction in some cases taking place via an intermediate with the formula

as in situ or, if desired, after insulation and external

further purification, can be cyclized to give the desired compound of formula (I).

In the preceding and in the following reaction schemes, W and W<*> mean a suitable leaving group, for example halogen such as chlorine, bromine or iodine, or a sulfonyloxy group such as methylsulfonyloxy or 4-methylphenylsulfonyloxy, while W can also be alkyloxy, alkylthio , Ar<2->0- or Ar<2->S-. X<3> in formulas (II) and (II-a) means 0, S or NH.

The piperidine, pyrrolidine or hexahydro-1H-azepine derivatives of formula (II) can be formed in situ, for example by conversion of piperidine, pyrrolidine or hexahydro-1H-azepine which is substituted with a -B-C-(=X<3>)- OH residue to an intermediate of formula (II) by reacting the former with thionyl chloride, phosphorus trichloride, phosphoryl chloride, polyphosphoric acid, phosphorus oxychloride and the like.

The reaction between (II) and (III) can be carried out in a suitable solvent such as a hydrocarbon such as benzene or hexane; an ether such as 1,1'-oxybisethane, tetrahydrofuran; a ketone such as 2-propanone, 2-butanone; an alcohol such as methanol, ethanol, 2-propanol, 1-butanol; a halogenated hydrocarbon such as trichloromethane, dichloromethane; an organic acid such as acetic acid, propanoic acid; a polar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; and mixtures of such solvents. Depending on the solvent and the nature of W, it may be appropriate to add a suitable base and/or iodide salt, preferably an alkali metal iodide, to the reaction mixture. Elevated temperatures can increase the reaction rate.

The compounds of formula (I) can also be prepared by

II.

reaction of a piperidine, pyrrolidine or hexahydro-1H-azepine with the formula

where M is hydrogen, an alkali or alkaline earth metal, with an intermediate of the formula

in a reaction-inert solvent.

The reactions between (IV-a) and (V-a) can conveniently be carried out in a suitable solvent, for example an aromatic hydrocarbon such as benzene, methylbenzene; an ether such as 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; a halogenated hydrocarbon such as trichloromethane and the like; N,N-dimethylformamide (DMF); N,N-dimethylacetamide (DMA) and where M is hydrogen, the solvent can also be a C 3 -alkanol such as methanol, ethanol, 1-butanol and the like; a ketone such as 2-propanone, 4-methyl-2-pentanone and the like. In some cases^ the addition of a suitable base such as an alkali metal carbonate or hydrogen carbonate, sodium hydride or an organic base such as N,N-diethylethanamine or N-(1-methylethyl)-2-propane and/or the addition of an iodine salt, preferably an alkali metal iodide, appropriate. Somewhat elevated temperatures can increase the reaction rate.

The compounds of formula (I) where B is -NH- can also be prepared by a cyclodesulfurization reaction of a suitable thiourea derivative of formula (VII) which can be formed in situ by condensation of an isothiocyanate of formula (VI) with a diamine of formula (III) ).

The cyclodesulfurization reaction can be carried out by reacting (VII) with a suitable alkyl halide, preferably iodomethane, in a suitable reaction-inert organic solvent, for example a lower alkanol such as methanol, ethanol, 2-propanol and the like. Furthermore, the cyclodesulfurization reaction can be carried out by reacting (VII) with a suitable metal oxide or salt in a suitable solvent according to known procedures. For example, the compounds of formula (I-b-1) can be easily prepared by reacting (VII) with a Hg(II) or Pb(II) oxide or a salt such as HgO, HgCl2, Hg(OAc)2, PbO or Pb(0Ac)2. In certain cases, it may be appropriate to supplement the reaction mixture with a small amount of sulphur, thus methanediimines and especially dicyclohexylcarbodiimide can be used as cyclodesulphurisation agent.

The compounds of formula (I) can also be prepared by N-alkylation of an intermediate of formula (VIII) with a suitable agent of formula (IX).

The N-alkylation reaction is conveniently carried out in an inert organic solvent such as, for example, an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene and the like; an alkanol such as methanol, ethanol, 1-butanol and the like; a ketone such as 2-propanone, 4-methyl-2-pentanone and the like; an ether such as 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; a polar aprotic solvent such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), nitrobenzene, 1-methyl-2-pyrrolidone and the like. The addition of a suitable base such as an alkali or alkaline earth metal carbonate, hydrogen carbonate, hydroxide and oxide, for example sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide and the like, or an organic base such as a tertiary amine such as N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, - 4-ethylmorpholine and the like can be used to capture the acid that is set free during the reaction. In some cases, the addition of an iodine salt, preferably alkali metal iodide, is appropriate. Somewhat elevated temperatures can increase the reaction rate.

The compounds of formula (I) can also be interconverted. Certain examples of such transformations will be described below.

To simplify the structural description of the compounds of formula (I) and of certain precursors and intermediates thereof will

hereafter represented by the symbol D.

The compounds of formula (I) where L is different from hydrogen, L being represented by L<1> and the compounds of formula (I-c), can generally be prepared by N-alkylation of a compound of formula (I) where L is hydrogen, being the compounds are represented by formula (I-d), with an agent of formula (X).

The N-alkylation is conveniently carried out according to known N-alkylation procedures described above for the preparation of (I) from (VIII) and (IX).

The compounds of formula (I) where L is C 8 -cycloalkyl, C 8 -alkyl, a residue of the formula (b-1), (b-2) or (b-3) where the residue L is represented by the residue L<2>H-, and the compounds are represented by formula (I-c-1), can also be prepared by the reductive N-alkylation reaction of (I-d) with a suitable ketone or aldehyde of formula L<2>=0 (XI), where L<2>=0 is an intermediate of formula L<2>H2 where two geminal hydrogen atoms are replaced by =0 and L<2>= is a geminal divalent residue comprising <C>3_6cycloalkylidene, C1_12alkylidene, R4-C1_Éjalkylidene, R<5->Y-C^alkylidene and R6 -Z 2 -C(=X )-Z 1 -C 1_6 alkylidene.

This reductive N-alkylation reaction can conveniently be carried out by catalytically hydrogenating a stirred and heated mixture of the reactants in a suitable reaction-initiated organic solvent according to known catalytic hydrogenation procedures. Suitable solvents are, for example, water; alkanols such as methanol, ethanol, 2-propanol and the like; cyclic ethers such as 1,4-dioxane and the like; halogenated hydrocarbons such as trichloromethane and the like; N,N-dimethylformamide; dimethyl sulfoxide and the like; or a mixture of two or more of these solvents. The term "known catalytic hydrogenation procedures" means that the reaction is carried out under hydrogen in the presence of a suitable catalyst such as palladium-on-charcoal, platinum-on-charcoal and the like. In order to prevent unwanted further hydrogenation of certain functional groups in the reactants and in the reaction products, it can be advantageous to add a suitable catalyst poison to the reaction mixture, for example thiophene and the like.

The compounds of formula (I) where L is a residue of formula (b-2) where R<5> is År<2> or Het, said R<5> being represented by R^~<a> and the compounds of formula ( I-c-2) can also be prepared by alkylating a compound of formula (I) where L is a residue of formula (b-2) in which R<5> is hydrogen, these compounds being represented by the formula (I-c-3), with a reagent of formula (XII).

The compounds of formula (I-c-2) can also be prepared by alkylating a compound of formula (I-c-4) with an agent of formula (XIII).

The alkylation reactions between (XII) and (I-c-3) and (XIII) with (I-c-4) can conveniently be carried out in an organic solvent such as, for example, an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene; a ketone such as 2-propanone, 4-methyl-2-pentanone; an ether such as 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran; and a polar aprotic solvent such as N,N-dimethylformamide (DMF); N,N-dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); nitrobenzene; 1-methyl-2-pyrrolidone; and such. Addition of a suitable base such as an alkali metal carbonate or hydrogen carbonate, sodium hydride or an organic base such as N,N-diethylethanamine or N-(1-methylethyl)-2-propanamine can be used to capture the acid that is set free during the reaction. Somewhat elevated temperatures can increase the reaction rate.

Compounds of formula (I) where L is a residue of formula (b-3) where Z<1> is NH and Z<2> is different from a direct bond whereby Z<2> is represented by Z<2_a> and the compounds by ( I—c—5) can be prepared by reacting an isocyanate or isothiocyanate of formula (I-c-6) with a reagent of the formula

(XIV).

The compounds of formula (I) where L is a residue of formula (b-3) where Z<2> is NH and Z<1> is different from a direct bond, in that Z<1> is represented by Z<1->a and the compounds of (I-c-7) can be prepared by reacting an isocyanate or isothiocyanate of formula (XV) with a compound of formula (I-c-8).

The reaction of (XIV) with (I-c-6) or (XV) with (I-c-8) is generally carried out in a suitable reaction-inert solvent such as, for example, an ether such as tetrahydrofuran and the like. Elevated temperatures may be suitable to increase the reaction rate.

The compounds of formula (I) where L is a residue of formula (b-3) where Z<2> is a direct bond and Z<1> is different from a direct bond in that the compounds are represented by (I-c-9), can be prepared by reacting an agent of formula (XVI) or a functional derivative thereof with a compound of (I-c-8).

The reaction of (XVI) with (I-c-8) can generally be carried out by following known esterification or amidation procedures. For example, the carboxylic acid can be converted into a reactive derivative, for example an anhydride or a carboxylic acid halide, which is then reacted with (I-c-8); or by reacting (XVI) and (I-c-8) with a suitable agent capable of forming amides or esters, for example dichlorohexyl carbodiimide, 2-chloro-1-methylpyridinium iodide or the like. These reactions are conveniently carried out in a suitable solvent such as an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, trichloromethane or a polar aprotic solvent. The addition of a base such as N,N-diethylethanamine may be suitable.

Reaction of an alkene of the formula L<3->C2_6alkenedlyl-H (XVII), where L<3> is phenyl, substituted phenyl or Het, with a compound of the formula H-D (I-d), is carried out in a reaction-initiated solvent to thereby produce a compound of the formula L<3->C2 alkandyl-D (I-c-10);

Reaction of a compound with formula R<25>

, where R<25> is

hydrogen or a residue R<7->0-CH2, with a compound of formula H-D (I-d), is carried out in a reaction-initiated solvent to thereby produce a compound of the formula R<25->CH(OH)-CH2- D (I-c-II); or

Cyclodesulfurization of a compound of the formula

with an alkyl halide, metal oxide or metal salt in a reaction-inert solvent to thereby produce a compound of the formula

The compounds of formula (I) can further be prepared by

a) Hydrolysis of a compound of the formula C^_(,alkyl-O-C(=O)-D in the presence of a base in an alcohol to obtain a

compound of the formula H-D (I-d);

b) hydrogenolysis of a compound of the formula benzyl-D in the presence of hydrogen in a reaction-initiated solvent

thereby obtaining a compound of the formula H-D (i-d);

c) reacting a compound of the formula benzyl-D with a C 1-6 alkyl carbonochloridate in a reaction-initiated solvent to thereby obtain a compound of the formula 6-alkyl-O-C(-O)-D; d) reducing a compound of the formula N<=>C-Alk-D with Raney nickel in an alcohol to thereby obtain a compound of the formula H2N-CH2~Alk-D; e) reacting a compound of the formula ^N-CB^-Alk-D with CS2 in a reaction-inert medium to thereby obtain a compound of the formula S=C=N-CH2-Alk-D; f) hydrolyzing an ester of the formula C 1-4 alkyl-O-CC-O)-Alk-D in an aqueous alkaline medium to thereby obtain a carboxylic acid of the formula HOOC-Alk-D; g) reducing a carbamate of the formula C^_£,-0-C(»0 )-D with lithium aluminum hydride in a reaction-inert medium to thereby obtain a compound of the formula CH3-D; h) alkylation or acylation of a compound of the formula with a compound of the formula W-r<1> where W means a reactive cleavable group, in a reaction-inert medium to thereby obtain a compound of the formula

i) hydrolyzing a compound of formula (I) where R<1>

means -Alk-O-C(-O)-C 1-4 alkyl in an alkaline medium to thereby obtain a compound where R 1 means -Alk-OH;

j) reacting a compound of formula (I) where R<1> means C 1-4 alkyloxycarbonyl in an alkaline medium to obtain a compound where R<1> means hydrogen;

k) hydrolyzing a compound of formula (I) where R<*>

means Alk-COOCi.^alkyl in an alkaline medium to thereby obtain a compound where R<*> means -Alk-COOH;

1) reduction of an intermediate with the formula

with Raney nickel in an alcohol to thereby obtain a compound of the formula

m) an alkylation of a compound of formula (I) where B

means NH with a reagent W-R<3>_<a> where W means a reactive leaving group and R<3>-a means C₁₋₀alkyl or benzyl in a reaction-initiated solvent to thereby give a compound where B means NR< 3->a,; or

optionally transforming the compounds of formula (I) into each other by following known transformation procedures for functional groups, and, if desired

conversion of the compounds of formula (I) into therapeutically active non-toxic acid addition salts by treatment with a suitable acid, or, conversely,

conversion of the acid addition salt to the free base form with alkali, and/or

preparation of stereochemically isomeric forms thereof.

In all of the preceding and following production methods, the reaction products can be isolated from the reaction mixture and, if desired, further purified according to generally known methods.

The compounds of formula (I) have basic properties and as a result they can be converted into the therapeutically active non-toxic acid addition salts by treatment with suitable acids, for example inorganic acids such as hydrochloric acid, hydrobromic acid and the like as well as sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as acetic, propane, hydroxyacetic, 2-hydroxypropane, 2-oxopropane, ethanedione, propanedione, butanedione, (Z)-2-butenedione, (E)-2-butenedione , 2-hydroxybutanedione-, 2,3-dihydroxybutanedione-, 2-hydroxy-1,2,3-propanetricarboxyl-, methanesulfone-, ethane-sulfone-, benzenesulfone-, 4-methylbenzenesulfone-, cyclohexane-sulfamine-, 2-hydroxybenzo -, 4-amino-2-hydroxybenzoic acid and the like. Conversely, the salt form can be converted by treatment with alkali into the free base form.

The compounds of formula (I) containing acidic protons can also be converted into the therapeutically active non-toxic metal-ene amine substitution salt forms by treatment with suitable organic or inorganic bases.

Certain intermediates and starting materials as described above are known compounds which can be prepared according to known methods for producing these or similar compounds and some of those mentioned are new. A number of such production methods will be described below in greater detail.

The intermediates of formula (II), where B is CEt, X<3> is NH and W is C1_^alkyloxy, compounds represented by formula (II-b), can be prepared by reacting a (cyanomethyl) derivative of formula (XIX ) with an alcohol such as methanol, ethanol and the like, in the presence of an acid such as hydrochloric acid.

The intermediates of formula (IV) can be prepared by reduction of a suitable 4-β-pyrrolidinone, 3-pyrrolidinone or hexahydro-1H-azepin-4-one, and if desired, followed by a known group transformation procedure, for example, in the case of a compound where (IV-b) is desired, by reacting the alcohol thus obtained with thionyl chloride, methylsulfonyl chloride and the like, in order to obtain a suitable cleavable group.

Starting substances such as the intermediates of formula (VIII), (X) and (XI) can be suitably prepared by following known procedures as described for example in US-PS 4 219 559, 4 335 127, 4 342 870, 4 443 451, 4 634 704, 4,695,569 and 4,588,722.

From formula (I) it is clear that the compounds according to the invention can have several asymmetric carbon atoms in the structure. Each of these chiral centers can be present in an R and an S configuration, the R and S charge being according to R.S. Cahn, C. Ingold and V. Prelog in "Angew. Chem.", Int. Ed. Engl., 5, 385, 511 (1966).

The pure stereochemically isomeric forms of the compounds of formula (I) can be obtained using known procedures. The diastereol isomers can be prepared by physical separation methods such as selective crystallization and chromatographic techniques, for example countercurrent distribution, and the enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids.

Pure stereochemically isomeric forms can also be obtained from the correspondingly pure stereochemically isomeric forms of the suitable starting materials, provided that the reaction takes place stereo-specifically.

It is clear that the cis- and trans-diastereomeric racemates can be further resolved into their optical isomers cis(+), cis(-), trans(+) and trans(-) using methods known per se.

Stereochemically isomeric forms of the compounds of formula (I) are within the scope of the invention.

The compounds of formula (I), the pharmaceutically acceptable acid addition salts thereof and possible stereochemically isomeric forms thereof have useful pharmacological properties. More particularly, they are effective as antihistamines with an activity that can be clearly demonstrated, for example, in a test aimed at protecting rats from compound 48/80 induced lethality, the test aimed at histamine antagonism in guinea pigs and the test aimed at ascaris allergy in dogs as described in " Arch. In. Pharmacodyn. Ther", 251. 39-51

(1981). Apart from the antihistaminic properties, some of the present compounds also show serotonin antagonism while others are active in the test against stress-cancer antagonism in rats related to the test described in "European Journal of Pharmacology", 137 (1987) 127-129.

In addition to this, the compounds of formula (I), the pharmaceutically acceptable acid addition salts thereof and stereochemically isomeric forms thereof are particularly attractive due to the favorable pharmacokinetic profile. In particular, some show a rapid onset of action so that their antihistamine effect is present almost immediately.

In light of the antibacterial properties, compounds of formula (I) and their acid addition salts are very useful in the treatment of allergic diseases such as, for example, allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma and the like.

The following examples are intended to illustrate the invention without limiting it. Unless otherwise stated, all quantities are by weight.

A. Production of intermediate products

Example 1

2350 parts hydrogen chloride was bubbled through 5600 parts ice bath cooled ethanol at ICC. Then 1,500 parts of 1-(phenylmethyl)-4-piperidineacetonitrile were added dropwise over the course of 45 minutes. After the addition was complete, the whole was stirred for 20 hours at room temperature. The reaction mixture was evaporated and the residue stirred in 2400 parts of acetonitrile. The product was filtered off, washed with 560 parts of acetonitrile and dried, giving 2000 parts corresponding to 85.7% of 0-ethyl-1-(phenylmethyl)-4-piper in dinetanimidate dihydrochloride (intermediate 1).

Example 2

a) A mixture of 46 parts of ethyl hexahydro-4-oxo-1H-azepine-1-carboxylate, 26 parts of benzenemethanamine, 2 parts of a 4*

solution of thiophene in methanol and 400 parts of methanol was hydrogenated at ordinary pressure and room temperature with 4 parts of 10# palladium-on-charcoal catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate evaporated, leaving 69.1 parts corresponding to 100* ethyl hexahydro-4-[(phenylmethyl)amino-1H-azepine-1-carboxylate as a residue ( intermediate product 2).

b) 69.1 parts of ethyl hexahydro-4-[(phenylmethyl)amino]-1H-azepine-1-carboxylate were hydrogenated using a

solution of 4* thiophene in methanol and methanol at usual

pressure and at room temperature with 4 parts 10* palladium-on-charcoal. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate evaporated, yielding 46.9 parts corresponding to 100* ethyl 4-amino-hexahydro-1H-azepine-1-carboxylate as a residue (intermediate 3) . c) 46.9 parts of ethyl-4-amino- hexahydro-1H-azepine-1-carboxylate. After the addition was complete, the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was evaporated and the residue stirred in 2,2'-oxybispropane. The precipitate was filtered off and the filtrate evaporated, yielding 70.75 parts corresponding to 100* ethyl hexahydro-4-isothiocyanato-1H-azepine-1-carboxylate as a residue (intermediate 4).

Example 3

To a stirred and cooled mixture of 4 parts of sodium hydroxide in 60 parts of water, 7.9 parts of carbon disulphide and 17.2 parts of ethyl 4-amino-1-piperidine carboxylate were successively added at a temperature below 10°C. Stirring was continued for 30 minutes at this temperature. Then 10.9 parts of ethyl carbon chloride were added dropwise (exothermic reaction: the temperature rises to approx. 35°C). After the reaction was complete, stirring was continued for 2 hours at 60°C. The reaction mixture was cooled and the product was extracted with methylbenzene. The extract was dried, filtered and evaporated to give 22 parts corresponding to 100* ethyl 4-isothiocyanato-1-piperidinecarboxylate as a residue (intermediate 5).

In a similar way, 4-isothiocyanato-1-(phenylmethyl)piperidine is also prepared as a residue (intermediate 6) and ethyl 3-isothiocyanato-1-pyrrolidine carboxylate as a residue (intermediate 7).

Example 4

a) A mixture of 19 parts of 2-chloro-3-nitropyridine, 13.5 parts of 2-ethoxyethanamine, 13 parts of sodium bicarbonate and 240

parts ethanol was stirred for 6 hours at reflux temperature. After cooling, the mixture was filtered over diatomaceous earth and the filtrate was evaporated, yielding 25.5 parts corresponding to 100* N-(2-ethoxyethyl)-3-nitro-2-pyridineamine as a residue (intermediate 8).

b) A mixture of 25.5 parts of N-(2-ethoxyethyl)-3-nitro-2-pyridinamine, 2 parts of a 4* solution of thiophene in

methanol and 200 parts of methanol were hydrogenated at normal pressure and at 50°C with 3 parts of 10* palladium-on-charcoal catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate evaporated, giving 25 parts corresponding to 100* N<2->(2-ethoxyethyl)-2,3-pyridinediamine as a residue (intermediate 9). c) A mixture of 25 parts of N<2->(2-ethoxyethyl)-2,3- pyridinediamine, 43 parts of ethyl 4-isothiocyanato-l-piperidine carboxylate and 450 parts of tetrahydrofuran were stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in trichloromethane. The organic layer was washed twice with water, dried, filtered and evaporated The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried to give 35 parts corresponding to 73.7* ethyl-4-[[[[2-[(2-ethoxyethyl)amino ]-3-pyridinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate as a residue (intermediate 10).

In the same way, it was also produced:

Example 5

a) A mixture of 37.5 parts of 4-isothiocyanate-1-methylpiperidine, 21.8 parts of 4-methoxy-1,2-benzenediamine and 270 parts

tetrahydrofuran was stirred and refluxed for 2 hours. The whole was evaporated and 44 parts corresponding to 100* N-(2-amino-5-methoxyphenyl)-N'-(1-methyl-4-piperidinyl)thiourea were obtained as a residue (intermediate 26).

b) A mixture of 44 parts N-(2-amino-5-methoxyphenyl)-N'-(1-methyl-4-piperidinyl)thiourea, 38.9 parts mercury (II) oxide

and 270 parts of tetrahydrofuran were stirred and refluxed for 2 hours at reflux temperature. The reaction mixture was filtered while warm over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using first trichloromethane:methanol (95:5 by volume) and then trichloromethane:ammonia-saturated methanol (85:15 by volume) as eluents. The pure fractions were pooled and the eluent was evaporated, yielding 50.5 parts corresponding to 100* 5-methoxy-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine as a residue (intermediate 27) .

In a similar manner, the following was also prepared: 5,6-dimethoxy-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine (intermediate 28).

Example 6

A mixture of 32 parts of 1-chloro-2-ethoxyethane, 94.5 parts of N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 90 parts of sodium carbonate and 540 parts of N,N-dimethylacetamide was stirred overnight at 70°C. After cooling, the reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was boiled in acetonitrile. After cooling, the precipitated product was filtered off and dried and 42.4 parts corresponding to 58.8* N-[1-(2-ethoxyethyl)-4-piperidinyl]-1H-benzimidazol-2-amine were obtained; melting point 212°C (intermediate 29).

Example 7

A mixture of 36.6 parts of N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 10 parts of poly(oxymethylene)", 2 parts of a 4* solution of thiophene in methanol, 200 parts of methanol and 20 parts of potassium hydroxide was hydrogenated at normal pressure and at room temperature with 4 parts of 10* palladium-on-charcoal catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate evaporated. The residue was treated with a sodium hydroxide solution. It precipitated product was filtered off and 13.7 parts corresponding to 59.4* N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine (intermediate 30) were obtained.

Example 8

To a stirred dispersion of 28.9 parts of ethyl 4-(1H-benz-imidazol-2-ylamino)-1-piperidinecarboxylate in 282 parts of N,N-dimethylformamide was added 4.8 parts of 50* sodium hydride dispersion under nitrogen (gas evolution , slightly exothermic reaction). The mixture was stirred for Vh hour at room temperature. 8.3 parts of chloroacetonitrile were added dropwise at ± 10°C while cooling in an ice bath. After the addition was complete, the temperature was allowed to reach room temperature and then stirred overnight. The reaction mixture was evaporated and the residue was taken up in water and 4-methyl-2 -pentanone. The separated organic layer was washed three times with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane-methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent evaporated. The residue was crystallized from methylbenzene, the product was filtered off and dried to give 12.4 parts corresponding to 37.8* ethyl-4-[[1-(cyano-methyl)-1H-benzimidazol-2-yl]amino]-1 -piperidine carboxylate as a residue (intermediate 31).

B. Preparation of end connections

Example 9

A mixture of 9 parts ethyl 4-[[[[2-[(2-ethoxyethyl)amino]-3-pyridinyl]amino]thioxomethyl]amino]-1-piperidine carboxylate, 13 parts mercury(II)oxide, 0.1 parts of sulfur and 120 parts of ethanol were stirred for 2 hours at reflux temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was converted to the hydrochloride salt in 2-propanone. The salt was filtered off and dried to yield 6.5 parts corresponding to 71.0* ethyl-4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino] -1-piperidine carboxylate in the form of a monohydrochloride; melting point 185.0°C (compound 1).

In a similar way, it was also produced:

and ethyl 4-[[3-[2-(diethylamino)ethyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate as a residue (compound 10).

Example 10

A mixture of 22.4 parts N-[4-[(2-ethoxyethyl)amino]-5-pyrimidinyl]-N'-[1-(phenylmethyl)-4-piperidinyl]thiourea, 17.3 parts mercury(II) oxide, 0.1 part sulfur and 270 parts tetrahydrofuran were stirred for 2 hours at reflux temperature. The reaction mixture was filtered while warm over diatomaceous earth. The filtrate was evaporated and the residue was purified by column chromatography over silica gel using trichloromethane/methanol in the ratio 95:5 as eluent. The pure fractions were pooled and the eluent evaporated, yielding 16.3 parts corresponding to 79.3* 9-(2-ethoxyethyl)-N-[1-(phenylmethyl)-4-piperidinyl]-9H-purin-8-amine as a residue (compound 11).

In a similar manner, it was also prepared: ethyl 4-[[1-(2-ethoxyethyl)-1H-imidazo[4,5-c]pyridin-2-yl]amino]-1-piperidinecarboxylate as a residue (compound 12 ); ethyl 4-[[3(2-ethoxyethyl)-3H-imidazo[4,5-c]pyridin-2-yl]amino]-1-piperidinecarboxylate as a residue (compound 13); ethyl 4-[[3-[(2-ethoxyethyl )-3H-imidazo[4,5-b]pyridin-2-yl]amino]hexahydro-1H-azepine-1-carboxylate as a residue (compound 14) and Methyl-(cis+ trans)-4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]amino]-3-methyl-1-piperidinecarboxylate as a residue ( connection 15).

Example 11

A mixture of 13 parts N-[2-[(2-ethoxyethyl)amino]-5-methylphenyl]-N<1->(1-methyl-4-piperidinyl)thiourea, 8.8 parts mercury(II)oxide and 90 parts of tetrahydrofuran were stirred for 1 hour at reflux temperature. The reaction mixture was filtered hot over diatomaceous earth and the filtrate evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:methanol 95:5 as eluent. The pure fractions were pooled and the eluent was evaporated. The residue was converted to the (E)-2-butenedioate salt in ethanol. The salt was filtered off and dried and 6.2 parts were obtained corresponding to 30.5* 1-(2-ethoxyethyl)-5-methyl-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine ( E)-2-butenedioate (1:2); mp 218.4"C (compound 16).

Example 12

A mixture of 120 parts of 0-ethyl-1-(phenylmethyl)-4-piperidine-ethanimidate dihydrochloride, 45.9 parts of 2-(2,3-diamino-2-pyridinyl)ethanol and 400 parts of methanol was stirred overnight at return temperature. A further portion of 60 parts of O-ethyl-1-(phenylmethyl)-4-piperidine tanimidate dihydrochloride was added and stirring was continued for 8 hours at reflux. After cooling, the reaction mixture was evaporated and the residue was taken up in water. The aqueous layer was treated with an ammonium hydroxide solution and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:ammonia-saturated methanol in a volume ratio of 95:5. The pure fractions were pooled and the eluent evaporated to give 87 parts corresponding to 82.7* 2-[[l-(phenylmethyl)-4-piperidinyl]methyl]-3H-imidazo-[4,5-b]pyridine-3 -ethanol as a residue (compound 17).

In a similar manner, it was also prepared: 3(2-ethoxyethyl)-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-3H-imidazo[4,5-b]pyridine as a residue (compound 18) .

Example 13

To a stirred solution of 34.64 parts of ethyl 4-hydroxy-1-piperidine carboxylate and 940 parts of N,N-dimethylformamide, 10 parts of 50* sodium hydride dispersion were added in portions at room temperature under nitrogen atmospheres. After the addition was complete, stirring was continued for 1 hour at room temperature. A solution of 45 parts of 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole in N,N-dimethylformamide was added dropwise by SCC. After the addition was complete, the whole was stirred overnight at 50°C. The reaction mixture was poured into ice water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated and 50 parts corresponding to 69.1* ethyl 4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]oxy]-1-piperidinecarboxylate were obtained as a residue (compound 19).

Example 14

A mixture of 14 parts of ethyl 4-[[3-(2-hydroxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate, 22 parts of potassium hydroxide and 160 parts of 2- propanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue taken up in water. The aqueous layer was salted out with potassium carbonate and the product was extracted with tetrahydrofuran. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried and 5.5 parts corresponding to 52.3* 2-(4-piperidinylamino)-3H-imidazo[4,5-b]-pyridine-3-ethanol were obtained; melting point 156.9°C (compound 20).

In a similar way, it was also produced:

and

N,N-dimethyl-2-(4-piperidinylamino)-1H-benzimidazole-1-ethanamine; mp 126.5°C (compound 32); N,N-diethyl-2-(4-piperidinylami.no )-3H-imidazo[4 , 5-b]pyridine-3-ethanamine (E )-2-butenedioate (1:3), melting point 180.8°C (compound 33); and

1-[(2-methoxyethoxy)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine; mp 148.5°C (compound 34).

Example 15

A mixture of 27 parts ethyl hexahydro-4-[[l-[2-(2-pyrimidinyloxy)ethyl]-1H-benzimidazol-2-yl]amino]-1E-azepine-1-carboxylate, 160 parts 1 -butanol, 28 parts potassium hydroxide and 2 parts water were stirred overnight at reflux temperature. The reaction mixture was diluted with water and the whole was extracted with 1-butanol. The extract was dried, filtered and evaporated. The residue was taken up in water and the product extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was converted to the (E)-2-butenedioate salt in ethanol. The salt was filtered off and dried and 9.77 parts were obtained corresponding to 38.5* 2-[(hexahydro-1H-azepin-4-yl)amino]-1H-benzimidazol-1-ethanol (E)-2-butenedioate ( 1:2); mp 176.1°C (compound 35).

In a similar way, it was also prepared: 3-(2-ethoxyethyl)-N-(hexahydro-1H-azepin-4-yl)-3H-imidazo-[4,5-b]pyridin-2-amine (E)- 2-butenedioate (2:3), melting point 180.0°C (compound 36).

Example 16

A mixture of 105 parts ethyl 4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]amino] hexahydro-1H-azepine-1-carboxylate, 79 parts potassium hydroxide and 833 parts 1,2-ethanediol was stirred overnight at reflux temperature. The reaction mixture was diluted in vacuo and the residue taken up in dichloromethane. The organic phase was filtered and the filtrate evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:methanol 90:10 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was converted to the ethanedioate salt. The salt was filtered off and crystallized from 2-propanol. The product was filtered off and dried and 16.4 parts corresponding to 9.9% of 1-(2-ethoxyethyl)-N-(hexahydro-1H-azepin-4-yl)-1H-benzimidazol-2-amine ethanedioate (1 :3), monohydrate (compound 37).

Example 17

A mixture of 140 parts of 2-[2-[2-[[l-(phenylmethyl)-4-piperidinyl]amino]-1H-benzimidazol-1-yl]ethoxy]ethanol and 480 parts of methanol was hydrogenated at ordinary pressure and room temperature with 5 parts 10* palladium-on-charcoal catalyst. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was crystallized twice from acetonitrile. The product was filtered off and dried and 53.3 parts corresponding to 46.0* 2-[2-[2-(4-piperidinylamino)-1H-benzimidazol-1-yl]ethoxy]ethanol were obtained; mp 163.7°C (compound 38).

In a similar way, the following was also prepared: 3-(2-ethoxyethyl)-2-(4-piperidinyl)-3H-imidazol [4,5-b]-pyridyl (E)-2-butenedioate (2:3); mp 177.9°C (compound 39); ethyl N-[2-[2-(4-piperidinylamino)-3H-imidazo[4,5-b]pyridin-3-yl]ethyl]glycine ethanedioate (1:3), dihydrate; mp 187.8°C (compound 40) and N-ethyl-N-[2-[2-(4-piperidinylamino)-3H-imidazo[4,5-b]pyridin-1-yl]ethyl]acetamide; mp 156.7°C (compound 41).

Example 18

A mixture of 16.3 parts of 9-(2-ethoxyethyl)-N-[1-(phenylmethyl)-4-piperidinyl]-9H-purin-8-amine and 200 parts of methanol was hydrogenated at ordinary pressure and room temperature with 4 parts 10* palladium-on-charcoal and 6 parts Raney nickel. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the filtrate evaporated. The residue was purified by column chromatography over silica gel using trichloromethane: ammonia-saturated methanol 90:10 by volume as eluent. The first fraction was collected and the eluent evaporated. The residue was converted to the (E)-2-butenedioate salt in methanol. The salt was filtered off and dried and 1.98 parts corresponding to 8,6* 9-(2-ethoxyethyl)-N-(4-piperidinyl)-9H-purine-8-amine ( E )-2-butenedioate were obtained (1:2), hemihydrate; melting point 192.8°C (compound 42).

Example 19

To a stirred and refluxed mixture of 13.5 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-3-[2-(2-propenyl-oxy)ethyl]-3H-imidazo[4 ,5-b]pyridine and 90 parts of methylbenzene, 5.4 parts of ethyl carbonochloridate were added dropwise. After the addition was complete, stirring was continued for 1 hour at reflux temperature. After cooling, the reaction mixture was diluted with water and the whole was treated with potassium carbonate. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated and 14 parts corresponding to 75.1* ethyl-4-[[3-[2-(2-propenyloxy)-ethyl]-3H-imidazo[4,5-b]pyridine were obtained -2-yl]methyl]-1-piperidinecarboxylate as a residue (compound 43).

Example 20

A mixture of 1.08 parts of 1-chloro-2-ethoxyethane, 2.9 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine , 1.06 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide were stirred overnight at 70°C. The reaction mixture was poured into water and the product extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by filtration over silica gel using trichloromethane:methanol 96:4 by volume as eluent. The pure fractions were pooled and the eluent evaporated. The residue was converted to the ethanedioate salt in methanol. The salt was filtered off and dried and 0.7 parts corresponding to 12.9* 3-(2-ethoxyethyl)-N-[1-(2-ethoxyethyl)]-N-[1-(2-ethoxyethyl)-4 were obtained -piperidinyl]-3H-imidazo[4,5-b]pyridin-2-amine ethanedioate (1:2); mp 176.1°C (compound 44).

In a similar way, it was also produced:

Using similar procedures, the following was also prepared: 1-[(2-methoxyethoxy)methyl]-N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine (E)-2-butenedioate (1:2 )/ melting point 164.0°C (compound 75) and

1-[(2-methoxyethoxy)-methyl I-N-[1-(2-ethoxyethyl]-4-piperidinyl]-1H-benzimidazol-2-amine E)-2-butenedioate (2:3 J/melt- point 160.2°C (compound 76).

Example 21

A mixture of 6 parts of 1-(2-bromomethyl)-1,3-dihydro-2H-benzimidazol-2-one, 7.63 parts of 2-[2-[2-(4-piperidinylamino)-3H-imidazo[4 ,5-b]pyridin-2-yl]ethoxy]ethanol, 3 parts sodium carbonate and 47 parts N,N-dimethylacetamide were stirred overnight at 70°C. After cooling, the reaction was poured into water and the product extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane: ammonia-saturated methanol in the volume ratio 95:5 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was recrystallized twice from 2-propanone. The product was filtered off and dried and 6.8 parts were obtained corresponding to 58.4* 1,3-dihydro-1-[2-[4-[ [3-[2-( 2-hydroxy et ok sy )ethyl] - 3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinyl]ethyl]-2H-benzimidazol-2-one; mp 177.0°C (compound 77).

In a similar way, it was also produced:

Example 22

A mixture of 3.1 parts of 2-thiophenethanol methanesulfonate(ester), 7 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3E-imidazo[4,5-b]-pyridin-2-amine ethanedioate ( 1:2), 1.6 parts of sodium carbonate and 75 parts of N,N-dimethylacetamide were stirred over at 80°C. The reaction mixture was poured into water and the product extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:methanol in the volume ratio 96:4 as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted to the ethanedioate salt in methanol. The salt was filtered off and dried to give 4.59 parts corresponding to 52.7* 3-(2-ethoxyethyl)-N-[1-[2-(2-thienyl)ethyl]-4-piperidinyl]-3H-imidazo -[4,5-b]-pyridine-2-amine ethanedioate (1:2), mp 218.2°C (compound 91).

Example 23

A mixture of 9.4 parts of 2-chloroacetonitrile, 30 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3E-imidazo[4 , 5-b]pyridin-2-amine, 11 parts of sodium carbonate and 658 portions of N,N-dimethylformamide was stirred over the weekend at room temperature. The reaction mixture is poured into water and the product extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:methanol in the volume ratio 97:3 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried in vacuo and 7.2 parts corresponding to 21.0* 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]amino were obtained ]-1-piperidineacetonitrile; melting point

141.4°C (compound 92).

In a similar way, it was also prepared: N-[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]-3-(2-ethoxyethyl)-3H -imidazo[4,5-b]pyridin-2-amine; mp 140.7 (compound 93);

3-(2-ethoxyethyl)-N-[1-[(4-methyl-1H-imidazo-5-yl)methyl]-4-piperidinyl]-3H-imidazo[4,5-b]pyridin-2-amine ; mp 187.9°C (compound 94);

ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino-1-piperidine acetate ethanedioate (1:2); mp 186.5°C (compound 95);

3-[2-[4-[[1-[2-(dimethylamino)ethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-methyl]-4H-pyrido[1, 2-α]pyrimidin-4-one ( E )-2-butenedioate (2:5) 2-propanolate (1:1); mp 174.6°C (compound 96);

3-[2-[4-[[3-[2-(diethylamino)ethyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino] -1 -piper i diny1]ethyl]- 2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (E)-2-butenedioate (1:2) monohydrate; m.p. 132.3°C (compound 97) and 6-[2-[4-[[3-(2-ethoxyethyl)-3H-Imidazo[4,5-b]pyridin-2-yl]methyl]-1- piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (E)-2-butenedioate (2:3) hemihydrate; mp 152.4°C (compound 98).

Example 24

A mixture of 3.7 parts of [(2-bromomethyl)sulfonyl]benzene, 4.34 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]-pyridine- 2-amine, 2.5 parts of sodium bicarbonate and 120 parts of ethanol were stirred for 2 hours at reflux temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was taken up in water and the product extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:methanol in the volume ratio 97:3 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was crystallized from a mixture of tetrahydrofuran and 2,2'-oxybispropane. The product was filtered off and dried and 2.6 parts were obtained corresponding to 37.5* 3-(2-ethoxyethyl)-N-[1-[2-(phenylsulfonyl)ethyl]-4-piperidinyl]-3H-imidazo- [4,5-b]-pyridine-2-amine hemihydrate; mp 101.9°C (compound 99);

In a similar way, it was also prepared: 3-(2-ethoxyethyl)-N-[1-[2-(phenylthio)ethyl]-4-piperidinyl]-3H-imidazo[4,5-b]pyridine-2- amine; mp 102.5°C (compound 100); 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-N-(1-methylethyl)-1-piperidinepropanamide; mp 163.7°C (compound 101); 3-(2-ethoxyethyl)-N-[1-(2-propenyl)-4-piperidinyl]-3H-imidazo[4,5-b]pyridin-2-amine ethanedioate (1:2); mp 183.8°C (compound 102) and 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl-N-(1-methylethyl)-1 -plperidinepropanamide; mp 97.8°C (compound 103).

Example 25

A mixture of 4.53 parts of chloroacetonitrile, 17.3 parts of 3-(2-ethoxyethyl)-2-(4-piperidinylmethyl)-3H-imidazo[4,5-b]pyridine, 6 parts of N,N-diethyl ethanamln and 94 portions of N,N-dimethylformamide was stirred for 3 hours at room temperature. The reaction mixture was poured into water and the product was extracted with 1,1'-oxyblethane. The extract was dried, filtered and evaporated, and 23.75 parts corresponding to 100* 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1 were obtained -piperidineaceto-nltrll as a residue (compound 104).

Example 26

To a stirred mixture of 2.6 parts of 2-(4-piperidinylamino)-3H-imidazo[4,5-b]pyridine-3-ethanol and 90 parts of N,N-dimethylformamide was added 0.5 parts of 50 * sodium hydride dispersion. After stirring for 30 minutes at room temperature, 1.2 parts of 3-bromo-1-propane were added dropwise while cooling. After the addition was complete, the stirring was continued for 1 hour. The reaction mixture was poured into water and the product extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane: ammonia-saturated methanol ammonia, in the volume ratio 96:4 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was converted to the ethanedioate salt in ethanol. The salt was filtered off and dried and one part was obtained corresponding to 20.7* 2 - [ [ 1- ( 2-pr openy 1)- 4-piper idi ny 1] amino] -3H-imidazo[4 ,5-b] - pyridine-3-ethanol ethanedioate (1:2); mp 188.4°C (compound 105).

Example 27

To a stirred and cooled to 0°C mixture of 4.34 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 1.53 parts of N,N-diethylethanamine and 130 parts of dichloromethane, 1.63 parts of ethyl carbonochloridate in dichloromethane were added dropwise. After the addition was complete, the temperature was allowed to rise to room temperature. The mixture was washed with water and the separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:ethanol in the volume ratio 95:5 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was converted to the (E)-2-butenedioate salt in ethanol. The salt was filtered off and dried to give 2.02 parts corresponding to 25.1* ethyl-4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino] -1-piperidine carboxylate ( E )-2-butenedioate (2:3); mp 153.8'C (compound 106).

In a similar way, it was also prepared: ethyl 4-[[1-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate ethanedioate (2:5) ; mp 157.5°C (compound 107).

Example 28

A mixture of 3 parts 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 3 parts poly(oxymethylene), 1 part of a 4* solution of thiophene in methanol, 120 parts of methanol and 5 parts of acetic acid, the potassium salt was hydrogenated at ordinary pressure and room temperature with 2 parts of 10* palladium-on-charcoal. After the calculated amount of hydrogen had been taken, the catalyst was filtered off over diatomaceous earth and the filtrate evaporated. The residue was taken up in water and treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was converted to the hydrochloride salt in 2-propanone and 2-propanol. The salt was filtered off and dried and 2 parts were obtained corresponding to 72.8* 3-(2-ethoxyethyl)-N-(1-methyl-4-piperidinyl)-3H-imidazo[4,5-b]pyridine-2- amine dihydrochloride; mp 260.4°C (compound 108).

In a similar way, it was also produced:

In a similar way, the following was also prepared: 1-[(2-methoxyethoxy)methyl]-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine (E)-2-butenedioate (1:2) /melting point 200.5°C (compound 118) and N-ethyl-N-[2-[2-[(1-methyl-4-piperidinyl )amino]-3H-imidazo-[4,5-b]pyridine- 1-yl]ethyl]acetamide (compound 119).

Example 29

A mixture of 28 parts of 2-(4-piperidinylamino)-3H-imidazo-[4,5-b]pyridine-3-ethanol, 20 parts of benzaldehyde, 2 parts of a 4* solution of thiophene in methanol and 160 parts of methanol was hydrogenated at ordinary pressure and room temperature with 3 parts 10* palladium-on-charcoal. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the filtrate evaporated. The residue was taken up in trichloromethane and the whole was extracted with an acidic aqueous solution. The extract was washed three times with trichloromethane and treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 1,1'-oxybisethane. The solid product was filtered off and dried and 25.2 parts corresponding to 65.1* 2-[[l-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo-[4,5-b]pyridine- 3-ethanol; melting point 125.7°C (compound 120).

In a similar way, it was also produced:

Example 30

A mixture of 2.4 parts of 2-bromo-5-methyl-1,3,4-thiadiazole, 5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-3-(2-ethoxyethyl)-3H -imidazo[4,5-b]-pyrldln-2-amine, 1.6 parts of sodium carbonate and 47 parts of N,N-dimethylacetamide were stirred overnight at 120°C. After cooling, the reaction mixture was poured into water and the product extracted with trichloromethane The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:ammonia-saturated methanol in the volume ratio 97:3 as eluent. The pure fractions were collected and the eluent evaporated. The residue was converted to the ethanedioate salt in ethanol. The salt was filtered off and dried and one obtained 1.23 parts corresponding to 13.2* 3-(2-ethoxyethyl)-N-[1-[2-[(5-methyl-1,3,4-thiadiazol-2-yl )amino]ethyl]-4-piperidinyl-3H-imidazo[4,5-b]-pyridin-2-amine ethanedioate (1:2), hemihydrate, mp 197.3°C (compound 129).

In a similar way, it was also prepared: N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyr in din-2-yl]methyl]-1- piperidinyl]ethyl]thiazol-2-amine (compound 130).

Example 31

A mixture of 1.7 parts of 2-chloropyrimidine, 4.33 parts of 4-[[3-(2-ethoxyethyl)-3H- im i dazo [4 , 5-b]-pyr i din-2-yl] methyl ] -1-piperidinethenamine, 1.7 parts sodium bicarbonate and 40 parts ethanol were stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane: ammonia-saturated methanol in the volume ratio 95:5. The pure fractions were pooled and the eluent evaporated. The residue was converted to the ethanedioate salt in a mixture of ethanol and 2-propanone. The salt was filtered off and dried to give 4.97 parts corresponding to 48.7* N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridine-2 -yl]methyl]-1-piperidinyl]ethyl]-2-pyrimidinamine ethanedioate (1:3); mp 119.7°C (compound 131).

In a similar manner was also prepared: 3-(2-ethoxyethyl)-N-[1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]-3H-imidazo[4,5-b]-pyridine- 2-amine; mp 149.6°C (compound 132).

Example 32

A solution of 5.5 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5 -b]-pyridin-2-yl]amino]-1-piperidineethanol in N,N-dimethylformamide. After the addition was complete, stirring was continued for 15 minutes at room temperature. 1.9 parts of 2-chloro-pyrimidine were added in portions and after the addition was complete, the stirring was continued for 2 hours at room temperature. The reaction mixture was decomposed with water and the product extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:methanol in the volume ratio 95:5. The pure fractions were pooled and the eluent evaporated. The residue was converted to the ethanedioate salt in ethanol. The salt was filtered off and dried to yield 3.4 parts corresponding to 34.8* 3-(2-ethoxyethyl)-N-[1-[2-(2-pyrimidinyl-oxy)ethyl]-4-piperidinyl] -3H-imidazo[4,5-b]-pyridin-2-amine ethanedioate (1:2); mp 185.7'C (compound 133).

In a similar way, it was also prepared: 3-(2-ethoxyethyl)-2-[[1-[2-(2-pyrimidinyloxy)ethyl]-4-piperidinyl]methyl]-3H-imidazo[4,5-b] -pyridine ethanedioate (1:2); mp 140.2°C (compound 134).

Example 33

A mixture of 1.5 parts isothiocyanate methane, 6.6 parts N-[1-(2-aminoethyl)-4-piperidinyl]-3-(2-ethoxyethyl)-3H-imidazo-[4,5-b]-pyridine -2-amine and 135 parts of tetrahydrofuran were stirred overnight at room temperature. The reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using trichloromethane: methanol in the volume ratio 96:4 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was converted to the ethanedioate salt in ethanol. The salt was filtered off and dried and 1.2 parts were obtained corresponding to 9.9* N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridine-2 -yl]amino-1-piperidinyl]-ethyl-N-methylthiourea ethanedioate (1:2), monohydrate; mp 166.8' C (compound 135).

Example 34

A solution of 8.6 parts of 4-[[ 3-(2-Ethoxyethyl)-3H-imidazo-[4,5-b]-pyridin-2-yl]methyl]-1-piperidinethanamine in tetrahydrofuran. After the addition was complete, the reaction mixture was stirred for 1 hour at room temperature. It was all evaporated and 11.2 parts were obtained corresponding to 3-(2-ethoxyethyl)-2-[[1-(2-isothiocyanatoethyl)-4-piper in dinyl]methyl]-3H-imidazo[4,5-b ] - pyridine as a residue (compound 136).

In a similar way, it was also prepared: 3-(2-ethoxyethyl)-N-[1-(2-isothiocyanatoethyl)-4-piper in dinyl]-3H-imidazo[4,5-b]-pyridine-2-amine as a residue (compound 137).

Example 35

A mixture of 3.3 parts of 3,4-pyridinediamine, 11.2 parts of 3-(2-ethoxyethyl)-2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-3H-imidazo[4, 5-b]-pyridine and 90 parts of tetrahydrofuran were stirred overnight at reflux temperature. The reaction mixture was evaporated and 14.5 parts corresponding to 100* N-(4-amino-3-pyridinyl)-N'-[2-[4-[[3-(2-ethoxyethyl )-3H-imidazo[4 , 5-b]-pyridin-2-yl]methyl]-1-piperidinyl]-ethyl]chlorurea as a residue (compound 138).

In a similar way was also prepared: N-(4-amlno-3-pyr Idinyl)-N'-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b] -pyridin-2-yl]amino]-1-piperidinyl]ethyl]thiourea as a residue (compound 139).

Example 36

A mixture of 14.5 parts of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridine -2-yl]methyl]-1-piperidinyl]ethyl]thiourea, 9.7 parts mercuric oxide and 90 parts tetrahydrofuran were stirred for 1 hour at reflux temperature. The reaction mixture was filtered hot over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using trichloromethane: ammonia-saturated methanol in the volume ratio 90:10 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was converted to the (E)-2-butenedioate salt in ethanol. The salt was filtered off and dried in a drying gun at 90°C and 6.78 parts corresponding to 24.5* N-[2-[4-[ [3-(2-ethoxyethyl )-3H-imidazo[4 .5 -b]-pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-1H-imidazo[4,5-c]-pyridin-2-amine (E)-2-butenedioate (1:4), hemihydrate ; mp 171.4°C (compound 140).

In a similar way, it was also prepared: 3-((2-ethoxyethyl)-N-[1-[2-[(1H-imidazo[4,5-c]-pyridin-2-yl)amino]ethyl] - 4-piper idi ny 1] -3H-imidazo[4,5-b]-pyr i din-2-amine (E)-2-butenedioate (2:9), m.p. 193.6°C (compound 141) .

Example 37

To a stirred mixture of 1.12 parts of 3-furancarboxylic acid, 2.02 parts of N,N-diethylethanamine and 195 parts of dichloromethane was added 2.6 parts of 2-chloro-1-methylpyridinium iodide at room temperature. After stirring for 1 hour, 3.3 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-amine added and the whole thing stirred overnight at room temperature. The mixture was poured into water and the layers separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane/methanol in the volume ratio 96:4 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was converted to the ethanedioate salt in ethanol. The salt was filtered off and dried to give 2.19 parts corresponding to 36.1* N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridine-2 -yl]amino]-1-piperidinyl]ethyl]-3-furancarboxamide ethanedioate (1:2); mp 160.7°C (compound 142).

In a similar way, the following was also prepared: N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]amino]-1-piperidinyl] ethyl]-1-methyl-1H-pyrrole-2-carboxamide ethanedioate (1:2); mp 188.0°C (compound 143); N-[2-[4-[[ 3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-2-thiazolecarboxamide; mp 116.7°C (compound 144); N-[2 - [4- [ [3-( 2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-3-furancarboxamide ethanedioate ( 1:1); mp 207.5°C (compound 145); and N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-1-methyl- 1H-pyrrole-2-carboxamide; mp 145.2°C (compound 146);

In a similar way, it was also prepared: 2-amino-N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyrldin-2-yl]methyl]- 1-piperidinyl]ethyl]benzamide (compound 147).

Example 38

Through a stirred mixture of 8.7 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]-pyridin-2-amine and 160 parts of methanol, oxirane was bubbled for 15 minutes. After stirring for 2 hours at room temperature, the mixture was evaporated. The residue was purified by column chromatography over silica gel with trichloromethane:ammonia-saturated methanol in a volume ratio of 95:5 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was stirred in 2,2*-oxybispropane. The product was filtered off and dried and 4.4 parts were obtained corresponding to 43.9* 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]amino]- 1-piperidineethanol; mp 94.3°C (compound 148).

In a similar way, it was also prepared: 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]methyl]-1-piperidineethanol (E)-2-butenedioate (2:3); mp 146.8°C (compound 149).

Example 39

A mixture of 5.4 parts 2-(phenoxymethyl)oxirane, 7.0 parts 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5—b]-pyridin-2-amine ethanedioate (1:2), 6.4 parts sodium carbonate and 64 parts 2-propanol were stirred for 20 hours at reflux temperature. The reaction mixture was evaporated and the residue taken up in water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:methanol in the volume ratio 95:5. The pure fractions were pooled and the eluent evaporated. The residue was converted to the hydrochloride salt in a mixture of 2-propanol and ethanol. The salt was filtered off and dried to give 3.1 parts corresponding to 40.3* 4-[[3-(2-ethoxyethyl)-3H-imidazo-[4,5-b]-pyridin-2-yl]amino] -α-(phenoxymethyl)-1-piperidine-ethanol dihydrochloride; melting point 250.7°C (compound 150).

Example 40

A mixture of 1.58 parts of 2-ethenylpyridine, 7 parts of 3-(2-isoethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]-pyrldin-2-amine ethanedioate (1:2), 1.8 parts sodium carbonate and 80 parts 1-butanol were stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue taken up in trichloromethane. The organic layer was washed twice with water, dried, filtered and evaporated. The residue was converted to the hydrochloride salt in 2-propanol. The salt was filtered off and dried in a drying gun at 100°C and 1.67 parts were obtained corresponding to 21.7* 3-(2-ethoxyethyl)-N-[1-[2-(2-pyridinyl)-ethyl]- 4-piperidinyl]-3H-imidazo[4,5-b]-pyridin-2-amine trihydrochloride, hemihydrate; mp 229.1°C (compound 151).

In a similar way, the following was also prepared: 3-(2-ethoxyethyl)-2-[[1-[2-(2-pyridinyl)ethyl]-4-piperidinyl]-methyl]-3H-imidazo[4,5-b ]-pyridine ethanedioate (1:3); mp 157.8°C (compound 152).

Example 41

0.75 parts of 50 *- ig sodium hydride dispersion under nitrogen. After stirring for 30 minutes at room temperature, a solution of 1.63 parts of 1-chloro-2-ethoxyethane in N.N-dimethylformamide was added dropwise to the resulting mixture at 50°C. After the addition was complete, stirring was continued overnight at 50°C. The reaction mixture was poured into water and the product extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel with trichloromethane: ammonia-saturated methanol in the volume ratio 98:2 on a volume basis as eluent. The pure fractions were pooled and the eluent evaporated. The residue was converted to the ethanedioate salt in ethanol. The salt was filtered off and dried and 3.2 parts corresponding to 39.5* of 1-(2-ethoxyethyl)-N-[1-(2-ethoxyethyl)-4-piperidinyl]-1H-benzimidazol-2-amine ethanedioate were obtained (1:2); mp 184.7°C (compound 153).

In a similar way, it was also produced:

and ethyl 4-[[1-[(methoxyethoxy)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp 102.2°C (compound 167).

Example 42

To a stirred mixture of 4.13 parts of 2-[(1-methyl-4-piperidinyl)amino]-3H-imidazo[4,5-b]-pyridine-3-ethanol and 90 parts of N,N-dimethylformamide 0.75 parts of 50 5é-ig sodium hydride dispersion was added. After stirring for 30 minutes at room temperature, 1.7 parts of 2-chloropyrimidine were added. The whole thing was stirred for 1 hour at room temperature and the reaction mixture completely in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried to give 1.7 parts corresponding to 32.0* N-(1-methyl-4-piperidinyl)-3-[2-(2-pyrimidinyloxy)-ethyl]-3H-imidazo[4, 5-b]-pyridin-2-amine; mp 158.1°C (compound 168).

In a similar manner was also prepared: N-(4-piperidinyl-3-[2-(2-pyrimidinyloxy)ethyl]-3H-imidazo-[4,5-b]-pyridin-2-amine ethanedioate (1:2 ), mp 172.4°C (compound 169); N -(1-methyl-4-piperidinyl)-3-[2-(2-propenyloxy)ethyl]-3H-imidazo[4,5-b]-pyridine -2-amine ethanedioate (1:2), mp 188.1°C (compound 170);

2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-3-[2-(2-propenyl-oxy)ethyl]-3H-imidazo[4,5-b]-pyridine as a residue (compound 171);

ethyl hexahydro-4-[[1-[2-(2-pyrimidinyloxy)ethyl]-1H-benz-imidazol-2-yl]amino]-1H-azepine-1-carboxylate as a residue (compound 172) and

N-(1-methyl-4-piperidinyl)-3-[2-(2-propynyloxy)ethyl]-3H-imidazo[4,5-b]-pyridin-2-amine (E)-2-butenedioate (1 :3); mp 196.2"C (compound 173).

Example 43

To a stirred solution of 11.9 parts of 2-[[l-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]-pyridine-3-ethanamine in 160 parts of N,N-dimethylf ormamide, 4.41 parts of ethyl carbonochloridate and 4.05 parts of N,N-diethylethanamine were added. The reaction mixture was heated slowly to 50°C and stirred first for 18 hours at this temperature and then for 18 hours at 70°C. The reaction mixture was evaporated and the residue taken up in a solution of sodium carbonate in water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:methanol in the volume ratio 90:10 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was converted to the ethanedioate salt in 2-propanol. The salt was filtered off and crystallized twice from ethanol. The product was filtered off and dried to yield 6.6 parts corresponding to 26.7* ethyl-N-[2-[2-[[1-(phenylmethyl)-4-piperidinyl]-amino]-3H-imidazo[4, 5-b]-pyridin-3-yl]ethyl]glycine ethanedioate (1:3); monohydrate; mp 169.5°C (compound 174).

Example 44

A mixture of 1.6 parts poly(oxymethylene), 8.1 parts ethyl 4-[[1-(2-amyl noethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate and 200 parts methanol was hydrogenated at ordinary pressure and room temperature with 2 parts of 10* palladium-on-charcoal catalyst. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the filtrate evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:ammonia-saturated methanol in the volume ratio 95:5 as eluent. The pure fractions were pooled and the eluent evaporated to give 9.2 parts corresponding to 100* ethyl 4-[[1-[2-(dimethylamino)ethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate as a residue (compound 175 ).

Example 45

7.8 parts of N-ethyl-2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]-pyridine-3-ethanamine were taken up in 75 parts of trichloromethane. 1.51 parts of acetic anhydride were added (exothermic reaction). The reaction mixture was stirred for 18 hours at room temperature. The whole was filtered over silica gel using trichloromethane: ammonia-saturated methanol in the volume ratio 95:5 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was taken up in methylbenzene and the whole evaporated again, giving 8.5 parts corresponding to 100* N-ethyl-N-[2-[2-[[l-(phenylmethyl)-4-piper in dinyl] amino]-3H-imidazo[4,5-b]-pyridin-3-yl]ethyl]acetamide as a residue (compound 176).

Example 46

A mixture of 2.7 parts of 50 µg sodium hydride dispersion and 282 parts of N,N-dimethylformamide was stirred at room temperature under nitrogen. 18.8 parts of ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]amino]-1-piperidinecarboxylate were added portionwise to this mixture. After the addition was complete, stirring was continued for 1 hour at room temperature. 10 parts of (bromomethyl)benzene were added dropwise after the addition was complete and stirring continued for 1 hour. The reaction mixture was decomposed with water and the product extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The rest was purified by column chromatography! over silica gel using trichloromethane:ethanol in the volume ratio 98:2. The pure fractions were pooled and the eluent evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried and 3.2 parts corresponding to 13.6* ethyl-4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl] ( phenylmethyl )amino]-1-piperidine carboxylate; mp 115.0°C (compound 177).

In a similar manner was also prepared: ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]methylamino]-1-piperidinecarboxylate as a residue (compound 178).

Example 47

A mixture of 23.75 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo-[4,5-b]-pyridin-2-yl]methyl]-1-piperidine acetonitrile and 400 parts of ammonia-saturated methanol was hydrogenated at ordinary pressure and room temperature with 6 parts Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate evaporated, yielding 22.7 parts corresponding to 100* 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b] -pyridin-2-yl]methyl]-1-piperidinethanamine as a residue (compound 179).

In a similar way, the following was also prepared: N-[1-(2-aminoethyl)-4-pyridinyl]-3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridine-2- amine as a residue (compound 180).

Example 48

A mixture of 10.4 parts of ethyl 4-[[1-(cyanomethyl)-1E-benzlmidazol-2-yl]amino]-1-piperidinecarboxylate and 160 parts of ammonia-saturated methanol was hydrogenated at ordinary pressure and room temperature with 2 parts of Raney- nickel catalyst. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the filtrate evaporated. The residue was purified by column chromatography over silica gel using trichloromethane:methanol in the volume ratio 90:10 as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted to the ethanedioate salt in 2-propanol. The salt was filtered off and crystallized from ethanol. The product was filtered off and dried and one obtained 6.5 parts corresponding to 39.5* ethyl 4-[[1-(2-aminoethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate ethanedioate (1: 2), monohydrate; mp 176.1°C (compound 181).

Example 49

A mixture of 5.5 parts of ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]amino]-1-piperidine acetate, 15 parts of an IN sodium hydroxide solution, 100 parts water and 16 parts ethanol were stirred overnight at room temperature. The reaction mixture was evaporated. The residue was taken up in water, washed with dichloromethane and purified by column chromatography! over silica gel using trichloromethane:ammonia-saturated methanol in the volume ratio 80:20, as eluent. The pure fractions were pooled and the eluent evaporated. The residue was recrystallized from 2-propanol. The product was filtered off and dried and one part was obtained corresponding to 19.1* 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]amino]-1- piperidine acetic acid; mp 227.3°C (compound 182).

Example 50

2.4 parts of a 50% sodium hydride dispersion were added portionwise to 147 parts of N,N-dimethylformamide under nitrogen. After the addition was complete, 12.5 parts of N-[1-(2-ethoxyethyl)-4-piperidinyl]-1H-benzimidazol-2-amine were added portionwise to the mixture. After the addition was complete, stirring was continued for 1 hour at room temperature. The whole was cooled and 9.85 parts of 2-(bromomethoxy)ethyl acetate were added (exothermic reaction). The reaction mixture was stirred for 2 hours at room temperature. The mixture was decomposed with water and the product extracted with trichloromethane. The extract was dried, filtered and evaporated. A mixture of the residue and 160 parts of ammonia-saturated methanol was stirred for 5 hours at room temperature. The mixture was evaporated and the residue was purified by column chromatography over silica gel using trichloromethane:ammonia-saturated methanol in the volume ratio 95:5 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried to give 0.98 parts corresponding to 6.3* 2-[2-[2-[[1-(ethoxyethyl)-4-piperidinyl]amino-1H-benzimidazol-1-yl]methoxy] ethanol; mp 109.0°C (compound 183).

In a similar manner, it was also prepared: ethyl 4-[[1-[(2-hydroxyethoxy)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp 142.8°C (compound 184) and

2- [ [2-[ [1- [2-(4-Methoxyphenyl)ethyl]-4-piperidinyl]amino]-1H-benzimidazol-1-yl]methoxy]ethanol; mp 142.0°C (compound 185).

In a similar manner was also prepared: 2-[[2-[(1-methyl-4-piperidinyl)amino]-1H-benzimidazol-1-yl]methoxy]ethanol (E )E-2-butenedioate (1:2 ); mp 192.1°C (compound 186).

Example 51

A mixture of 20 parts of ethyl [2-[2-[[l-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]-pyridin-3-yl]ethyl]carbamate, 26.3 parts of potassium hydroxide and 200 parts of 2-propanol were stirred for VA hour at reflux temperature. The reaction mixture was evaporated and the residue taken up in water. It all evaporated again. The residue was taken up in a small amount of water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane: ammonia-saturated methanol in the volume ratio 90:10 as eluent. The pure fractions were pooled and the eluent evaporated. The residue was boiled in 2,2'-oxybispropane (+ activated charcoal) and the whole was filtered over diatomaceous earth. The filtrate was allowed to crystallize. The crystallized product was filtered off, the filtrate set aside, and dried, giving a first fraction of 6.7 parts corresponding to 40.6* 2-[[l-(phenylmethyl)-4-piperidinyl]amino]-3H -imidazo[4,5-b]-pyridine-3-ethanamine. The filtrate set aside was evaporated to give a second fraction of 6.6 parts corresponding to 40.0* 2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5- b]-pyridine-3-ethanamine, total yield 13.3 parts corresponding to 80.6* 3-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]-pyridine -3-ethanamine; mp 101.7°C (compound 187). addition, stirring was continued for 1 hour at reflux temperature. After cooling, the reaction mixture was decomposed with ethyl acetate, a 15% sodium hydroxide solution and 5 parts water. It was all filtered and over diatomaceous earth and the filtrate was evaporated. The rest was purified by column chromatography! over silica gel using trichloromethane: methanol: ammonia-saturated methanol in the volume ratio 95:2.5:2.5, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted to the (E)-2-butenedioate salt in 2-propanol. The salt was filtered off and dried and 3.2 parts corresponding to 40.5* 3-(2-ethoxyethyl)-N-methyl-N-(1-methyl-4-piperidinyl)-3H-imidazo-[4, 5-b]-pyridin-2-amine ( E )-2-butenedioate (2:5); mp 153.5°C (compound 192).

In a similar way, the following was also prepared: 3-(2-ethoxyethyl)-N-(1-methyl-4-piperidinyl)-N-(phenylmethyl)-3H-imidazo[4,5-b]-pyridin-2-amine -hemihydrate; mp 68.3°C (compound 193).

C. Pharmacological trials

The useful antihistamine properties of the compounds of formula (I) are shown in the following test procedure.

Protection of rats against compound 48/80-induced lethality

Compound 48/80, a mixture of oligomers obtained by condensation of 4-methoxy-N-methylbenzenetanamine and formaldehyde is described as a potent histamine-releasing agent ("Inst. Arch. Allergy", 13, 336 (1958)). Protection from compound 48/80-induced lethal circulatory collapse appears to be a simple way to quantitatively assess the antihistamine activity of test compounds. Male rats of an inbred Wistar strain with a body weight of 240-260 g were used. After fasting overnight, the rats were transferred to conditioned laboratories (temperatures 21 ± 1°C, relative humidity 65 ± In a similar way, it was also prepared: N--ethyl-2- [ [1-(phenylmethyl)-4-piperidinyl] amino ] -3H-imidazo-[4,5-b]-pyridine-3-ethanamine trihydrochloride, mp 279.4°C (compound 188).

Example 52

To a stirred solution of 3.46 parts of ethyl-N-[2-[2-(4-piperidinylamino)-3H-imidazo[4,5-b]-pyridin-3-yl]ethyl]glycine and 25 parts of water was 1.12 parts of potassium hydroxide were added. After stirring for 18 hours at room temperature, the reaction mixture was washed with dichloromethane and acidified with concentrated hydrochloric acid. The whole was evaporated to dryness and the residue purified by reverse phase chromatography (HPLC) over "Li Chroprep RP 18" using a mixture of 80* methanol and 20* water containing 0.25* ammonium acetate as eluent. The desired fraction was collected and the eluent evaporated. The residue was converted to the hydrochloride salt in 2-propanol, ethanol and hexane. The salt was dried and 1.18 parts were obtained corresponding to 26.4* N-[2-[2-(4-piperidinylamino)-3H-imidazo[4,5-b]-pyridin-3-yl] ethyl]glycine- dihydrochloride, trihydrate; mp 242.6°C (compound 189).

In a similar way, it was also prepared: oc-[2-[2-[(1-methyl-4-piperidinyl)amino]-3H-imidazo[4,5-b]-pyridin-3-yl]ethyl]oxy] acetic acid; mp 214.8°C (compound 190) and α-[2-[2-[[l-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo-[4,5-b]-pyridine-3- yl]ethyl]oxy]acetic acid ^H 2 O; mp 140.1'C (compound 191).

Example 53

To a stirred mixture of 21 parts of 1M lithium tetrahydro-aluminate solution in 1,1'-oxybisethane in 45 parts of tetrahydrofuran was added dropwise a solution of 4.9 parts of ethyl-4-[[3-(2-ethoxyethyl)-3H-imidazo [4,5-b]-pyridin-2-yl]methylamino]-1-piperidinecarboxylate in 45 parts of tetrahydrofuran during 10 minutes under nitrogen. After completion 5*). The rats were treated subcutaneously or orally with a test compound or with the solvent (0.9* NaCl solution). One hour after treatment, compound 48/80, freshly dissolved in water, was injected intravenously in an amount of 0.5 mg/kg (0.2 ml/100 g body weight). In control experiments in which 250 solvent-treated animals were injected with the standard dose of compound 48/80, no more than 2.8* of the animals survived after 4 hours. Survival after 4 hours is therefore considered a reliable criterion for a protective effect of drug administration. The ED5Q values for the compounds according to formula (I) are given in Table 1. These are values in mg/kg body weight at which the tested compounds protected 50* of the tested animals against compound 48/80-induced lethality.

Claims (1)

Analogous process for the preparation of a therapeutically active compound of the formula a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, where -A^=A<2->A<3=>A<4-> is a divalent residue of the formula where one or two hydrogen atoms in the residues (a-1) to (a-7) independently of each other may be replaced by halogen, C1-5 alkyl or C1-6 alkyloxy; R<1> is hydrogen; C 6 -6 alkenyl optionally substituted with phenyl; C 3-6 alkynyl; phenyl; substituted phenyl; pyrimidinyl; or C^_^alkyl which is optionally substituted with phenyl, substituted phenyl, thienyl, furanyl, C^fcalkyl substituted furanyl, pyridinyl, pyrimidinyl, hydroxy, Ci-^alkyloxy, carboxyl, C^-^alkyloxy carbonyl, phenoxycarbonyl or benzyloxy carbonyl; G is 0, S or NR<2>; where R<2 > is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl or benzyl; B is NR<3>, CH2 or 0; wherein R<3> is hydrogen, C^_^alkyl or benzyl; R is hydrogen or C 1-4 alkyl; n is 0, 1 or 2; L is hydrogen, C3-5 alkyloxycarbonyl, C3-5 cycloalkyl, C2-6 alkenyl which is optionally substituted with phenyl, C1-4 alkyl or a residue of the formula there R<4> is phenyl, substituted phenyl, Het or cyano; R<5> is hydrogen, phenyl, substituted phenyl, Het or c^_^~ alkyl; R<6 > is hydrogen, phenyl, substituted phenyl, Het or C 1-6 )-alkyl; R<7> is phenyl, substituted phenyl or naphthalenyl; Y is 0, S or NH; Z<1> and Z<2> are each independently 0, S, NH or a direct bond; X is 0 or S; each Alk independently is C^_^alkanediyl; substituted phenyl is phenyl substituted with halogen, hydroxy, amino, C 1-4 alkyloxy or C 1-4 alkyl; Het is pyridinyl optionally substituted with halogen, amino, C 1-4 alkyl or hydroxy; pyrimidinyl which is optionally substituted with halogen, amino, hydroxy or C 1-6 alkyl; thienyl; furanyl; pyrrolyl optionally substituted with C 1-6 alkyl; thiazolyl optionally substituted with C 1-6 alkyl; imidazolyl optionally substituted with C 1-4 alkyl; tetrazolyl which is optionally substituted with C 1-6 alkyl; 1,3,4-thiadiazolyl which is optionally substituted with C 1-4 alkyl; 4,5-dihydro-5-oxo-1H-tetrazolyl which is optionally substituted with C 1-6 alkyl; 2,3-dihydro-1,4-benzodioxynyl; 2-oxo-2H-1-benzopyranyl or a bicyclic residue of the formula there G<2> is -CH=CH-CH=CH-, -S-(CH2)2-, -S-(CH2)3-, -(CH2)4-, -S-CH=CH- or -S -CH=C(CH3)-; and R 17 is C 1-6 alkyl; provided that when L is hydrogen, C 1-4 alkyl or benzyl and R 2 -G-Alk is <C> 4-alkyloxyethyl, C 3-4alkenyloxyethyl or phenoxyethyl, then -A<1>=A<2->A<3 =>A<4-> different from a bivalent residue of the formula -CH=CH-CH=CH-, characterized byI. reaction of a piperidine, pyrrolidine or hexahydro-1H-azepine with the formula where X<3> is 0, S or NE and W is a reactive leaving group, with an aromatic diamine of the formula in a reaction-inert medium, as the reaction in some cases takes place via an intermediate product with the formula which in situ or if desired, after isolation and further purification, can be ring-closed to give the desired compound of formula (I); II. reaction of a piperidine, pyrrolidine or hexahydro-1E-azepine with the formula where M is hydrogen, an alkali or alkaline earth metal, with an intermediate of the formula in a reaction-inert solvent; III. cyclodesulfurization of an intermediate of the formula which can be prepared in situ by condensation of an isothiocyanate with the formula with a diamine of the formula (III), with an alkyl halide, metal oxide or metal salt in a reaction-inert solvent; IV. N-alkylation of an intermediate of the formula with a connection with the formula where W<1> is a reactive cleavable group, in a reaction-inert medium; V. a) N-alkylation of a compound of the formula H-D (I-d) there D means a remainder with the formula where A<1>, A<2>, A<3>, A<4>, B, G, R, R<1> and N have the above meaning, with a compound of the formula iA<->W< 1 >(X) where W<*> is a reactive cleavable group, in a reaction-inert solvent, to thereby produce a compound of formula I^-D (I-c) where IA has the meaning given above for L, provided that it is different from hydrogen; b) reductively N-alkylating a compound of the formula H-D (I—d) with a ketone or an aldehyde of the formula L<2>=0 (XI) , where L<2>=0 is an intermediate of the formula L<2 >H2 where two geminal hydrogen atoms are replaced by =0, in a reaction-inert medium to thereby produce a compound with the formula L<2>H-D (I-c-1); where L<2> is a geminal divalent residue comprising C8_^cycloalkylidene, alkylidene, R<4->C1_6alkylidene, R^Y-C^alkylidene and R6-Z2-C(=X J-Zi-C^alkylidene; c) alkylation of a compound of the formula H-Y-Alk-D (I-c-K _ o •* 3) with an intermediate of the formula R -W-<1> (XII), where jj5-a is phenyl, substituted phenyl or Het, in a reaction-initiated solvent, thereby producing a compound of the formula R<5>-a<->Y-Alk-D (I-c-2); d) reacting a compound of the formula R^~Z<2_a>—H (XIV) where Z<2_a> is 0, S or NH, with a compound of the formula X=C=N-Alk-D (I-c-6 ), in a reaction-inert solvent, thereby producing a compound of the formula R6-Z2_<a->C(=X)-NH-Alk-D (I-c-5); e) reacting an isocyanate or isothiocyanate of the formula r<6->N=C=X (XV) with a compound of the formula H-Z<1_a->Alk-D (I-c-8), where Z<1>-a is 0, S or NH, in a reaction-inert solvent, thereby producing a compound of the formula R<6->NH-C(=X)-Z1_a-Alk-D (I-c-7); f) reacting a compound of the formula R<6->C(=X)-OH (XVI) with a compound of the formula H-Z<1>-a<->Alk-D (I-c-8) in a reaction-inert solvent, if desired, after converting the OH group in (XVI) into a reactive cleavable group or by reacting (XVI) with (I-c-8) in the presence of a compound capable of forming esters or amides, thereby producing a compound with the formula R^-C(=X)-Z1"a-Alk-D (I-c-9); g) reaction of an alkene with the formula L3-C2_É,alkenediyl-H (XVII), where L<3> is phenyl, substituted phenyl or Het, with a compound of the formula H-D (I-d), in a reaction-inert solvent to thereby prepare a compound of the formula L<3->C2alkandlyl-D (I-c-10); h) reacting a compound with the formula R<2>^ , where R<2>^ is hydrogen or a residue R<7->0-CH2, with a compound of the formula H-D (I-d) in a reaction-initiated solvent to thereby prepare a compound of the formula R<2>^-CH( OH)-CH 2 -D (I-c-II); or i) cyclodesulfurization of a compound of the formula with an alkyl halide, metal oxide or metal salt in a reaction-inert solvent to thereby produce a compound of formula VI. a) hydrolyzing a compound of the formula C 1-4 alkyl-O-C(=O)-D in the presence of an alcohol to thereby obtain a compound of the formula H-D (I-d); b) hydrogenolysis of a compound of the formula benzyl-D in the presence of hydrogen in a reaction-inert solvent to obtain a compound of the formula H-D (I-d); c) reacting a compound of the formula benzyl-D with a C 1-6 alkylcarbonochloridate in a reaction-inert solvent to thereby obtain a compound of the formula <G>1-6 alkyl-O-C(=O)-D; d) reducing a compound of the formula N=C-Alk-D with Raney alkyl in an alcohol to thereby obtain a compound of the formula <H>2N-CH2-Alk-D; e) reacting a compound of the formula H2N-CH2-Alk-D with CS2 in a reaction-inert medium to thereby obtain a compound of the formula S=C=N-CH2-Alk-D; f) hydrolyzing an ester of the formula C 1 -5 alkyl-O-C(=O)-Alk-D in an aqueous alkaline medium to thereby obtain a carboxylic acid of the formula HOOC-Alk-D; g) reducing a carbamate of the formula C_£,alkyl-O-C(=O )-D with lithium aluminum hydride in a reaction-inert medium to thereby give a compound of the formula CH 3 -D; h) alkylation or acylation of a compound of the formula with a compound of formula W-R<1> where W means a reactive cleavable group, in a reaction-inert medium, to thereby obtain a compound of formula i) hydrolyzing a compound of formula (I) where R<1 >means -Alk- 0-C(=0J-Cj.^alkyl in an alkaline medium to thereby obtain a compound where R<1> means -Alk-OH; j) reaction of a compound (I) where R<1> means C^. ^alkyloxycarbonyl in an alkaline medium to thereby obtain a compound where R<1> means hydrogen; k) hydrolyzing a compound of formula (I) in which R<1 >means Alk-COOCi.^alkyl in an alkaline medium to thereby obtain a compound in which R<1> means -Alk-COOH; 1) reduction of an intermediate with the formula with Raney nickel in an alcohol to thereby obtain a compound of formula m) N-alkylation of a compound of formula (I) where B means NH, with a compound W-R<3>_<a> where W means a reactive cleavable group and R<3>-a means C₁₋alkyl or benzyl in a reaction-initiated solvent to thereby obtain a compound where B means NR<3_a>; or optionally transforming the compounds of formula (I) into each other by following known transformation procedures for functional groups, and, if desired conversion of the compounds of formula (I) into therapeutically active non-toxic acid addition salts by treatment with a suitable acid, or, conversely, conversion of the acid addition salt to the free base form with alkali, and/or preparation of stereochemically isomeric forms thereof.